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Full text of "lippincott's receptor for life family"

LIFE FAMILY 



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LIFE FAMILY WE HERE FOR YOU 

Chapter 2 

Drug"Receptor Interactions and 
Pharmacodynamics 

I. Overview 

Most drugs exert their effects, both beneficial and 
harmful, by interacting with receptorsa€"that is, 
specialized 

target macromoleculesa€"present on the cell 
surface or intracellular^. Receptors bind drugs and 
initiate events 

leading to alterations in biochemical and/or 
biophysical activity of a cell, and consequently, the 
function of an 

organ (Figure 2.1). Drugs may interact with 
receptors in many different ways. Drugs may bind 
to enzymes (for 




LIFE FAMILY WE HERE FOR YOU 

example, inhibition of dihydrofolate reductase by 
trimethoprim, see p. 394), nucleic acids (for 
example, blockade 

of transcription by dactinomycin, see p. 469), or 
membrane receptors (for example, alteration of 
membrane 

permeability by pilocarpine, see p. 49). In each 
case, the formation of the druga€"receptor 
complex leads to a 

biologic response. Most receptors are named to 
indicate the type of drug/chemical that interacts 
best with it; for 

example, the receptor for histamine is called a 
histamine receptor. Cells may have tens of 
thousands of receptors 

for certain ligands (drugs). Cells may also have 
different types of receptors, each of which is 
specific for a 




LIFE FAMILY 



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particular ligand. On the heart, for example, there 
are I 2 receptors for norepinephrine, and muscarinic 
receptors 

for acetylcholine. These receptors dynamically 
interact to control vital functions of the heart. The 
magnitude of 

the response is proportional to the number of drug 
"receptor complexes" 



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LIFE FAMILY WE HERE FOR YOU 

This concept is closely related to the formation of 
complexes between enzyme and substrate, or 
antigen and 

antibody; these interactions have many common 
features, perhaps the most noteworthy being 
specificity of the 

receptor for a given ligand. However, the receptor 
not only has the ability to recognize a ligand, but 
can also 

couple or transduce this binding into a response by 
causing a conformational change or a biochemical 
.effect 

Although much of this chapter will be centered on 
the interaction of drugs with specific receptors, it 
is important t 

be aware that not all drugs exert their effects by 
interacting with a receptor; for example, antacids 
chemically 




LIFE FAMILY WE HERE FOR YOU 

neutralize excess gastric acid, reducing the 
symptoms of a€oeheartburn.a€ This chapter 
introduces the study of 

pharmacodynamicsa€"the influence of drug 
concentrations on the magnitude of the response. 
It deals with the 

interaction of drugs with receptors, the molecular 
consequences of these interactions, and their 
effects in the 

.patient 

A fundamental principle of pharmacodynamics is 
that drugs only modify underlying biochemical and 
physiological 

.processes; they do not create effects de novo 

II. Chemistry of Receptors and Ligands 

Interaction of receptors with ligands involves the 
formation of chemical bonds, most commonly 
electrostatic and hydrogen bonds, as well as weak 




LIFE FAMILY WE HERE FOR YOU 

interactions involving van der Waals forces. These 
bonds are important in 

determining the selectivity of receptors, because 
the strength of these noncovalent bonds is related 
inversely to 

the distance between the interacting atoms. 
Therefore, the successful binding of a drug requires 
an exact fit of the 

ligand atoms with the complementary receptor 
atoms. The bonds are usually reversible, except for 
a handful of 

drugs (for example, the nonselective l±-receptor 
blocker phenoxybenzamine, and 
acetylcholinesterase inhibitors in 

the organophosphate class) that covalently bond 
to their targets. The size, shape, and charge 
distribution of the 




LIFE FAMILY WE HERE FOR YOU 

drug molecule determines which of the myriad 
binding sites in the cells and tissues of the patient 
can interact with 

the ligand. The metaphor of the a€oelock and 
keya€ is a useful concept for understanding the 
interaction of 

receptors with their ligands. The precise fit 
required of the ligand echoes the characteristics of 
€the a€oekey,a 

whereas the opening of the a€oelocka€ reflects 
the activation of the receptor. The interaction of 
the ligand with 

its receptor thus exhibits a high degree of 
specificity. The induced-fit model has largely 
replaced the lock-and-key 

concept as the preferred model describing the 
interaction of a receptor and a ligand. In the 
^presence of a ligand 




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the receptor undergoes a conformational change 
to bind the ligand. The change in conformation of 
the receptor 

caused by binding of the agonist activates the 
receptor, which leads to the pharmacologic effect. 
This model suggests that the receptor is flexible, 
not rigid as implied by the lock-and-key model 



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LIFE FAMILY WE HERE FOR YOU 

. Major Receptor Families 

Pharmacology defines a receptor as any biologic 
molecule to which a drug binds and produces a 
measurable 

response. Thus, enzymes and structural proteins 
can be considered to be pharmacologic receptors. 
However, the 

richest sources of therapeutically exploitable 
pharmacologic receptors are proteins that are 
responsible for 

transducing extracellular signals into intracellular 
responses. These receptors may be divided into 
(four families: 1 

ligand-gated ion channels, 2) G proteina€"coupled 
receptors, 3) enzyme-linked receptors, and 4) 
intracellular 

receptors (Figure 2.2). The type of receptor a 
ligand will interact with depends on the nature of 
.the ligand 




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Hydrophobic ligands interact with receptors that 
are found on the cell surface (families 1, 2, and 3). 
<ln contrast 

hydrophobic ligands can enter cells through the 
lipid bilayers of the cell membrane to interact with 
receptors found inside the cell "family4" 



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A. Ligand-gated ion channels 

The first receptor family comprises ligand-gated 
ion channels that are responsible for regulation of 
the flow of ions 



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LIFE FAMILY WE HERE FOR YOU 

across cell membranes (see Figure 2.2A). The 
activity of these channels is regulated by the 
binding of a ligand to the 

channel. Response to these receptors is very rapid, 
having durations of a few milliseconds. The 
nicotinic receptor 

and the l 3 -aminobutyric acid (GABA) receptor are 
important examples of ligand-gated receptors, the 
functions of 

which are modified by numerous drugs. 
Stimulation of the nicotinic receptor by 
acetylcholine results in sodium 

influx, generation of an action potential, and 
activation of contraction in skeletal muscle. 
Benzodiazepines, on the 

other hand, enhance the stimulation of the GABA 
receptor by GABA, resulting in increased chloride 
influx and 






LIFE FAMILY WE HERE FOR YOU 

hyperpolarization of the respective cell. Although 
not ligand-gated, ion channels, such as the voltage- 
gated sodium 

channel, are important drug receptors for several 
.drug classes, including local anesthetics 

B. G proteina€"coupled receptors 

A second family of receptors consists of G 
proteina€"coupled receptors. These receptors are 
comprised of a single 

peptide that has seven membrane-spanning 
regions, and these receptors are linked to a G 
(protein (Gs and others 

having three subunits, an l± subunit that binds 
guanosine triphosphate (GTP) and a l 2 l 3 subunit 
(Figure 2.3). Binding 

of the appropriate ligand to the extracellular 
region of the receptor activates the G protein so 
that GTP replaces 



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LIFE FAMILY WE HERE FOR YOU 

guanosine diphosphate (GDP) on the l± subunit. 
Dissociation of the G protein occurs, and both the 
l±-GTP subunit 

and the l 2 l 3 subunit subsequently interact with 
other cellular effectors, usually an enzyme or ion 
channel. These 

effectors then change the concentrations of 
second messengers that are responsible for further 
actions within the 

cell. Stimulation of these receptors results in 
.responses that last several seconds to minutes 

Second messengers: These are essential in .1 
conducting and amplifying signals coming from G 
proteina€"coupled 

receptors. A common pathway turned on by Gs, 
and other types of G proteins, is the activation of 
adenylyl 



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LIFE FAMILY WE HERE FOR YOU 

cyclase by l±-GTP subunits, which results in the 
production of cyclic adenosine monophosphate 
(cAMP)a€"a 

second messenger that regulates protein 
phosphorylation. G proteins also activate 
phospholipase C, which is 

responsible for the generation of two other second 
messengers, namely inositol-l,4,5-trisphosphate 
and 

diacylglycerol. These effectors are responsible for 
the regulation of 

P.28 

intracellular free calcium concentrations, and of 
other proteins as well. This family of receptors 
transduces 

signals derived from odors, light, and numerous 
neurotransmitters, including norepinephrine, 
<dopa-mine 




LIFE FAMILY WE HERE FOR YOU 

serotonin, and acetylcholine. G proteina€"coupled 
receptors also activate guanylyl cyclase, which 
converts 

GTP) to cyclic guanosine monophosphate (cGMP), ) 
a fourth second messenger that stimulates cGMP- 
dependent 

protein kinase. cGMP signaling is important in only 
a few cells, for example, intestinal mucosa and 
vascular 

smooth muscle, where it causes relaxation of 
vascular smooth muscle cells. Some drugs such as 
sildenafil 

produce vasodilation by interfering with specific 
phosphodiesterases, the enzymes that 
metabolically break 

.down cGMP 

C. Enzyme-linked receptors 






LIFE FAMILY WE HERE FOR YOU 

A third major family of receptors consists of those 
having cytosolic enzyme activity as an integral 
component of 

their structure or function (see Figure 2.2C). 
Binding of a ligand to an extracellular domain 
activates or inhibits this 

cytosolic enzyme activity. Duration of responses to 
stimulation of these receptors is on the order of 
minutes to 

hours. The most common enzyme-linked receptors 
(epidermal growth factor, platelet-derived growth 
factor, atrial 

natriuretic peptide, insulin, and others) are those 
that have a tyrosine kinase activity as part of their 
.structure 

Typically, upon binding of the ligand to receptor 
subunits, the receptor undergoes conformational 
changes. converting from its inactive form to an 






LIFE FAMILY WE HERE FOR YOU 

active kinase form. The activated receptor 
autophosphorylates, and 

phosphorylates tyrosine residues on specific 
proteins. The addition of a phosphate group can 
substantially modify 

the three-dimensional structure of the target 
protein, thereby acting as a molecular switch. For 
example, when the 

peptide hormone insulin binds to two of its 
receptor subunits, their intrinsic tyrosine kinase 
activity causes 

autophosphorylation of the receptor itself. In turn, 
the phosphorylated receptor phosphorylates 
target 

moleculesa€"insulin-receptor substrate 
peptidesa€"that subsequently activate other 
important cellular signals such 






LIFE FAMILY 



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as IP3 and the mitogen-activated protein kinase 
system. This cascade of activations results in a 
multiplication of the 

initial signal, much like that which occurs with G 
protein "coupled receptors" 




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D. Intracellular receptors 

The fourth family of receptors differs considerably 
from the other three in that the receptor is entirely 
intracellular 

and, therefore, the ligand must diffuse into the cell 
to interact with the receptor (Figure 2.4). This 
places 

constraints on the physical and chemical 
properties of the ligand in that it must have 
sufficient lipid solubility to be 

able to move across the target cell membrane. 
Because these receptor ligands are lipid soluble, 
they are 

transported in the body attached to plasma 
proteins, such as albumin. For example, steroid 
hormones exert their 

action on target cells via this receptor mechanism. 
Binding of the ligand with its receptor follows a 
general pattern 






LIFE FAMILY WE HERE FOR YOU 

in which the receptor becomes activated because 
of the dissociation of a small repressor peptide. 
The activated 

liganda€"receptor complex migrates to the 
nucleus, where it binds to specific DNA sequences, 
resulting in the 

regulation of gene expression. The time course of 
activation and response of these receptors is much 
longer than 

that of the other mechanisms described above. 
Because gene expression and, therefore, protein 
synthesis is 

modified, cellular responses are not observed until 
considerable time has elapsed (thirty minutes or 
more), and the 

duration of the response (hours to days) is much 
.greater than that of other receptor families 

P.29 






LIFE FAMILY WE HERE FOR YOU 

IV. Some Characteristics of Receptors 

A. Spare receptors 

A characteristic of many receptors, particularly 
those that respond to hormones, 
neurotransmitters, and peptides, is 

their ability to amplify signal duration and 
intensity. The family of G proteina€"linked 
receptors exemplifies many of 

the possible responses initiated by ligand binding 
to a receptor. Specifically, two phenomena 
account for the 

amplification of the liganda€"receptor signal. First, 
a single liganda€"receptor complex can interact 
with many G 

proteins, thereby multiplying the original signal 
many-fold. Second, the activated G proteins persist 
for a longer 



© 



LIFE FAMILY WE HERE FOR YOU 

duration than the original liganda€"receptor 
complex. The binding of albuterol, for example, 
may only exist for a 

few milliseconds, but the subsequent activated G 
proteins may last for hundreds of milliseconds. 
Further 

prolongation and amplification of the initial signal 
is mediated by the interaction between G proteins 
and their 

respective intracellular targets. Because of this 
amplification, only a fraction of the total receptors 
for a specific 

ligand may need to be occupied to elicit a maximal 
response from a cell. Systems that exhibit this 
behavior are said 

to have spare receptors. Spare receptors are 
exhibited by insulin receptors, where it has been 
estimated that 99 



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LIFE FAMILY WE HERE FOR YOU 

percent of the receptors are a€oespare.a€ This 
constitutes an immense functional reserve that 
ensures adequate 

amounts of glucose enter the cell. On the other 
end of the scale is the human heart, in which about 
five to ten 

percent of the total ^-adrenoceptors are spare. An 
important implication of this observation is that 
little functional 

reserve exists in the failing heart; most receptors 
must be occupied to obtain maximum contractility 



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B. Desensitization of receptors 

Repeated or continuous administration of an 
agonist (or an antagonist) may lead to changes in 
the responsiveness of 

the receptor. To prevent potential damage to the 
cell (for example, high concentrations of calcium, 
initiating cell 



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LIFE FAMILY WE HERE FOR YOU 

death), several mechanisms have evolved to 
protect a cell from excessive stimulation. When 
repeated 

administration of a drug results in a diminished 
effect, the phenomenon is called tachyphylaxis. 
The receptor 

becomes desensitized to the action of the drug 
(Figure 2.5). In this phenomenon, the receptors are 
still present on 

the cell surface but are unresponsive to the ligand. 
Other types of desensitization occur when 
receptors are 

down-regulated. Binding of the agonist results in 
molecular changes in the membrane-bound 
receptors, such that 

the receptor undergoes endocytosis and is 
sequestered from further agonist interaction. 
These receptors may be 






LIFE FAMILY WE HERE FOR YOU 

recycled to the cell surface, restoring sensitivity, or 
alternatively, may be further processed and 
'degraded 

decreasing the total number of receptors available. 
Some receptors, particularly voltage-gated 
channels, require a 

finite time (rest period) following stimulation 
before they can be activated again. During this 
recovery phase they 

are said to be a€oeref ractorya€ or 
€a€oeunresponsive.a 

C. Importance of the receptor concept 

It is important that we understand the roles and 
functions of receptors because most drugs interact 
with receptors 

that will determine selective therapeutic and toxic 
effects of the drug. Moreover, receptors largely 
determine the 






LIFE FAMILY WE HERE FOR YOU 

quantitative relations between dose of a drug and 
pharmacologic effect. 

V. Dosea€"Response Relationships 

An agonist is defined as an agent that can bind to a 
receptor and elicit a biologic response. The 
magnitude of the 

drug effect depends on the drug concentration at 
the receptor site, which in turn is determined by 
the dose of drug 

administered and by factors characteristic of the 
drug pharmacokinetic profile, such as rate of 
absorption distribution, and metabolism. 






LIFE FAMILY 



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A. Graded dosea€"response relations 

As the concentration of a drug increases, the 
magnitude of its pharmacologic effect also 
increases. The relationship 




LIFE FAMILY WE HERE FOR YOU 

between dose and response is a continuous one, 
and it can be mathematically described for many 
systems by 

application of the law of mass action, assuming the 
simplest model of drug binding 

The response is a graded effect, meaning that the 
response is continuous and gradual. This contrasts 
with a quantal 

response, which describes an all-or-nothing 
response. A graph of this relationship is known as a 
graded 

dosea€"response curve. Plotting the magnitude of 
the response against increasing doses of a drug 
produces a graph 

that has the general shape depicted in Figure 2.6A. 
The curve can be described as a rec-tangular 
hyperbolaa€"a very 






LIFE FAMILY WE HERE FOR YOU 

familiar curve in biology, because it can be applied 
to diverse biological events, such as ligand binding, 
enzymatic 

.activity, and responses to pharmacologic agents 

Potency: Two important properties of drugs can .1 
be determined by graded dosea€"response curves. 
The first is 

potency, a measure of the amount of drug 
necessary to produce an effect of a given 
magnitude. For a number 

of reasons, the concentration producing an effect 
that is fifty percent of the maximum is used to 
determine 

potency; it commonly designated as the EC50. In 
Figure 2.6, the EC50 for Drugs A and B are 
indicated. Drug A is 

more potent than Drug B because less Drug A is 
needed to obtain 50 percent effect. Thus, 
therapeutic 






LIFE FAMILY WE HERE FOR YOU 

preparations of drugs will reflect the potency. For 
example, candesartan and irbesartan are 

angiotensina€"receptor blockers that are used 
alone or in combination to treat hypertension. 
Candesartan is 

more potent than irbesartan because the dose 
range for candesartan is 4 to 32 mg, as compared 
to a dose range 

of 75 to 300 mg for irbesartan. Candesartan would 
be Drug A and irbesartan would be Drug B in Figure 
2.6. An 

important contributing factor to the dimension of 
.the EC50 is the affinity of the drug for the receptor 

Semilogarithmic plots are often employed, 
because the range of doses (or concentrations) 
may span several 

orders of magnitude. By plotting the log of the 
concentration, the complete range of doses can be 
graphed. As 



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LIFE FAMILY WE HERE FOR YOU 

shown in Figure 2.6B, the curves become sigmoidal 
in shape. It is also easier to visually estimate the 
.EC50 

Efficacy [intrinsic activity]: The second drug .2 
property that can be determined from graded 
dosea€"response 

plots is the efficacy of the drug. This is the ability 
of a drug to illicit a physiologic response when it 
interacts 

with a receptor. Efficacy is dependent on the 
number of druga€"receptor complexes formed and 
the efficiency 

of the coupling of receptor activation to cellular 
responses. Analogous to the maximal velocity for 
-enzyme 

catalyzed reactions, the maximal response (Emax) 
or efficacy is more important than drug potency. A 
drug with greater efficacy is more therapeutically 






LIFE FAMILY WE HERE FOR YOU 

beneficial than one that is more potent. Figure 2.7 
shows the response 

.to drugs of differing potency and efficacy 

Drug receptor binding: The quantitative . 
relationship between drug concentration and 
receptor occupancy 

applies the law of mass action to the kinetics of the 
binding of drug and receptor molecules. By making 
the 

assumption that the binding of one drug molecule 
does not alter the binding of subsequent 
molecules, we can 

mathematically express the relationship between 
the percentage (or fraction) of bound receptors 
and the drug concentration 



> ■:•!&-:.■■ , 







LIFE FAMILY WE HERE FOR YOU 

where [D] = the concentration of free drug; [DR] = 
the concentration of bound drug; [Rt] = the total 
concentration of receptors, and is equal to the sum 
of the concentrations of unbound (free) receptors 
and 

bound receptors and; Kd = [D][R]/[DR], and is the 
dissociation constant for the drug from the 
receptor. The 

value of Kd can be used to determine the affinity 
of a drug for its receptor. Affinity describes the 
strength of 

the interaction (binding) between a ligand and its 
receptor. The higher the Kd value, the weaker the 
interaction 

and the lower the affinity. The converse occurs 
when a drug has a low Kd. The binding of the 
ligand to the 



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LIFE FAMILY WE HERE FOR YOU 

receptor is strong, and the affinity is high. Equation 
(1) defines a curve that has the shape of a 
rectangular 

hyperbola (Figure 2.8). As the concentration of free 
drug increases, the ratio of the concentrations of 
bound 

receptors to total receptors approaches unity. 
Doses are often plotted on a logarithmic scale, 
because the range 

from lowest to highest concentrations of doses 
often spans several orders of magnitude. It is 
important to note 

the similarity between these curves and those 
representing the relationship between dose and 
effect. 






LIFE FAMILY 



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Relationship of binding to effect: The binding of .4 
the drug to its receptor initiates events that 
ultimately lead to 

a measurable biologic response. The mathematical 
model that describes drug concentration and 
receptor 






LIFE FAMILY WE HERE FOR YOU 

binding can be applied to dose (drug 
concentration) and response (or effect), providing 
the following 

assumptions are met: 1) The magnitude of the 
response is proportional to the amount of 
receptors bound or occupied, 2) the Emax occurs 
when all receptors are bound, and 3) binding of 
the drug to the receptor exhibits no cooperativity. 
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re when all recep Lois ate bound Kan 



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LIFE FAMILY 



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Agonists: If a drug binds to a receptor and .5 
produces a biologic response that mimics the 
response to the 

endogenous ligand, it is known as an agonist. For 
example, phenylephrine is an agonist at l±l- 
<adrenoceptors 

because it produces effects that resemble the 

action of the endogenous ligand, norepinephrine. 
Upon binding to l±l-adrenoceptors on the 
membranes of 




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vascular smooth muscle, phenylephrine mobilizes 
intracellular Ca , causing contraction of the actin 
and myosin filaments. The shortening of the 
muscle cells decreases the diameter of the 
arteriole, causing an increase in resistance to the 
flow of blood through the vessel. Blood pressure 
therefore rises to maintain the blood flow. As this 
brief description illustrates, an agonist may have 
many effects that can be measured, including 
actions on intracellular molecules, cells, tissues, 
and intact organisms. All of these actions are 
attributable to interaction 

of the drug molecule with the receptor molecule. 
In general, a full agonist has a strong affinity for its 
receptor and good efficacy. 



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Drug SArJtK non- 
competitive 
antagonist 



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Antagonists: Antagonists are drugs that .6 
decrease the actions of another drug or 
endogenous ligand. Antagonism 

may occur in several ways. Many antagonists act 
on the identical receptor macromolecule as the 
.agonist 

Antagonists, however, have no intrinsic activity 
and, therefore, produce no effect by themselves. 
Although 

antagonists have no intrinsic activity, they are able 
to bind avidly to target receptors because they 



possess 



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strong affinity. If both the antagonist and the 
agonist bind to the same site on the receptor, they 
are said to be 

a€oecompetitive.a€ For example, the 
antihypertensive drug prazosin competes with the 
^endogenous ligand 

norepinephrine, at l±l-adrenoceptors, decreasing 
vascular smooth muscle tone and reducing blood 
.pressure 

Plotting the effect of the competitive antagonist 
characteristically causes a shift of the agonist 
dosea€"response 

curve to the right. Competitive antagonists have 
no intrinsic activity. If the antagonist binds to a site 
other than 

where the agonist binds, the interaction is 
a€oenoncompetitivea€ or a€oeallosterica€ (Figure 
2.9). [Note: A 






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drug may also act as a chemical antagonist by 
combining with another drug and rendering it 
inactive. For example, protamine ionically binds to 
heparin, rendering it inactive and antagonizing 
Functional .7heparin's anticoagulant effect 
antagonism: An antagonist may act at a completely 
separate receptor, initiating effects that are 

functionally opposite those of the agonist. A classic 
example is the antagonism by epinephrine to 
-histamine 

induced bronchoconstriction. Histamine binds to 
HI histamine receptors on bronchial smooth 
muscle, causing contraction and narrowing of the 
bronchial tree. Epinephrine is an agonist at l 2 2- 
adrenoceptors on bronchial smooth muscle, which 
causes the muscles to actively relax. This 
functional antagonism is also known as physiologic 
antagonism. 



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. Partial agonists: Partial agonists have efficacies 8. 
(intrinsic activities) greater than zero, but less than 
that of a 

full agonist. Even if all the receptors are occupied, 
partial agonists cannot produce an Emax of as 
great a 

magnitude as that of a full agonist. However, a 
partial agonist may have an affinity that is greater 
than, less 

than, or equivalent to that of a full agonist. A 
unique feature of these drugs is that, under 
appropriate 






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conditions, a partial agonist may act as an 
antagonist of a full agonist. Consider what would 
happen to the Emax 

of an agonist in the presence of increasing 
concentrations of a partial agonist (Figure 2.10). As 
the number of 

receptors occupied by the partial agonist increases, 
the Emax would decrease until it reached the Emax 
of the 

partial agonist. This potential of partial agonists to 
act both agonistically and antagonistically may be 

.therapeutically exploited 

For example, aripiprazole, an atypical neuroleptic 
agent, is a partial agonist at selected dopamine 
.receptors 

Dopaminergic pathways that were overactive 
would tend to be inhibited by the partial agonist, 
whereas 



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pathways that were underactive may be 
stimulated. This might explain the ability of 
aripiprazole to improve 

many of the symptoms of schizophrenia, with a 
small risk of causing extrapyramidal adverse 
(effects (see p. 33 

VI. Quantal Dosea€"Response Relationships 

Another important dosea€"response relationship 
is that of the influence of the magnitude of the 
dose on the 

proportion of a population that responds. These 
responses are known as quantal responses, 
because, for any 

individual, the effect either occurs or it does not. 
Even graded responses can be considered to be 
quantal if a 

predetermined level of the graded response is 
designated as the point at which a response occurs 
or not. For 






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example, a quantal dosea€"response relationship 
can be determined in a population for the 
antihypertensive drug 

atenolol. A positive response is defined as at least 
a 5 mm Hg fall in diastolic blood pressure. Quantal 

dosea€"response curves are useful for determining 
doses to which most of the population responds 



Warfarin : S m a 1 1 
therapeutic index 



Therapeutic 




Log concentration of 

drug .n |>I - 1 ii -i 
{arbitrary units! 



Penicil/im Large 
therapeutic index 




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A. Therapeutic index 






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The therapeutic index of a drug is the ratio of the 
dose that produces toxicity to the dose that 
produces a clinically 

desired or effective response in a population of 
individuals: 



where TD50 = the drug dose that produces a toxic 
effect in half the population and ED50 = the drug 
dose that produces a therapeutic or desired 
response in half the population. The therapeutic 
index is a measure of a drug's safety, because a 
larger value indicates a wide margin between 
.doses that are effective and doses that are toxic 

B. Determination of therapeutic index 

The therapeutic index is determined by measuring 
the frequency of desired response, and toxic 
response, at various doses of drug. By convention, 
the doses that produce the therapeutic effect and 
the toxic effect in fifty percent of the population 






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are employed; these are known as the ED50 and 
TD50, respectively. In humans, the therapeutic 
index of a drug is determined using drug trials and 
accumulated clinical experience. These usually 
reveal a range of effective doses and a different 
(sometimes overlapping) range of toxic doses. 
Although some drugs have narrow therapeutic 
indices, they are routinely used to treat certain 
diseases. Several lethal diseases, such as Hodgkin's 

lymphoma, are treated with narrow therapeutic 
index drugs; however, treatment of a simple 
headache, for example, with a narrow therapeutic 
index drug would be unacceptable. Figure 2.11 
shows the responses to warfarin, an oral anti- 
coagulant with a narrow therapeutic index, and 
penicillin, an antimicrobial drug with a large 

Warfarin (example of a drug .1 therapeutic index 
with a small therapeutic index): As the dose of 
warfarin is increased, a greater fraction of the 
patients respond (for this drug, the desired 




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response is a two-fold increase in prothrombin 
time until eventually, all patients respond (see 
Figure 2. HA). However, at higher doses of 
namely a high 'warfarin, a toxic respons occurs 
degree of anticoagulation that results in 
hemorrhage. [Note: that when the therapeutic 
index is low, it is possible to have a range of 
concentrations where the effective and toxic 
some patients 'responses overlap. That is 
hemorrhage, whereas others achieve the desired 
.two-fold prolongation of prothrombin time 

Variation in patient response is, therefore, most 
likely to occur with a drug showing a narrow 
therapeutic index because the effective and toxic 
concentrations are similar. Agents with a low 
therapeutic index that is, drug 

for which dose is critically important "are those 
drugs for which bioavailability critically alters the 
.(therapeutic effects 



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Penicillin (example of a drug with a large .2 
therapeutic index): For drugs such as penicillin (see 
^(Figure 2.11B 

it is safe and common to give doses in excess 
(often about ten-fold excess) of that which is 
minimally required t 

achieve a desired response. In this case, 
bioavailability does not critically alter the 
.therapeutic effects 

Study Questions 

.Choose the ONE best answer 

?Which of the following statements is correct 2.1 

A. If 10 mg of Drug A produces the same response 
as 100 mg of Drug B, Drug A is more efficacious 
than Drug 

B. The greater the efficacy, the greater the potency 
.of a drug 






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C. In selecting a drug, potency is usually more 
.important than efficacy 

.D. A competitive antagonist increases the ED50 

E. Variation in response to a drug among different 
individuals is most likely to occur with a drug 
showing a 

.large therapeutic index 

Variation in the sensitivity of a population of 2.2 
individuals to increasing doses of a drug is best 
determined b 

?which of the following 

.A. Efficacy 

.B. Potency 

.C. Therapeutic index 

.D. Graded dose "response curve 

.E. Quantal dose "response curve 



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Which of the following statements most 2.3 
accurately describes a system having spare 
^receptors 

A. The number of spare receptors determines the 
maximum effect 

.B. Spare receptors are sequestered in the cytosol 

C. A single drug "receptor interaction results in 
many cellular response elements being activated 

D. Spare receptors are active even in the absence 
.of agonist 

E. Agonist affinity for spare receptors is less than 
their affinity for non spare receptors 






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